Mechanism of neuropathogenesis. Two components of this mechanism are: A) the direct effect of the HIV-1 infection, including HIV-1 proteins and B) the indirect consequence of infection comprising the secretion of cytokines and neurotoxins. The infected macrophages and microglia participate actively in the neurodegeneration by: 1) shedding viral proteins and 2) releasing significant amount of cytokines and neurotoxins into the CNS. 3) Tat and TNF-α contribute to the disruption of the blood brain barrier, which in turn become more permeable to infected monocytes and cytokines present in the periphery. The secreted pro-inflammatory cytokines activates 4) microglia and 5) astrocytes which in turn secrete neurotoxins, moreover the alteration of astrocytes function results in an increase in the level of neurotoxicity in the brain. 6) Multifactorial neuronal injury: neurotoxins released from several sources, as the direct and indirect consequences of HIV-1 infection, lead to neuronal injury.